The pathology of cerebral ischemia is divided into the hyperacute stage (about 3 hours from the onset) and the acute stage (about 2 weeks from the onset). The cerebral ischemic neuronal cell death is known to relate to excitatory amino acid toxicity and free radical. In the excitatory amino acid toxicity, a cellular disorder is developed in the hyperacute stage due to calcium influx associated with release of glutamic acid caused by energy disorders and binding of the acid to its receptor, and inflammation reaction occurs in the acute stage (non-patent document 1). As for free radical, its increase or hypoxic condition induces expression of an inflammatory gene (proinflammatroy gene) via production of a transcription factor such as transcription Nuclear factor KB (hereinafter NF-κB), Hypoxia-inducible transcription factor-1 (hereinafter HIF-1), Signal transducer and activator of transcription 3 (hereinafter STAT3) and the like (non-patent document 2). Through these mechanisms, inflammatory cytokines such as tumor necrosis factor-α (hereinafter TNF-α), Interleukin-1β (hereinafter IL-1β), interleukin-6 (hereinafter IL-6) and the like are produced. These cytokines are considered to advance symptoms such as brain edema and inflammatory cell infiltration, and encourage neurological deficit.
At present, as a drug showing neuroprotection against ischemia, only Edaravon that traps free radical (hydroxy radical) can be mentioned, which is used for treating cerebral infarction (atherothrombotic brain infarction, lacunar infarction, cardioembolic stroke). On the other hand, although ion channel (Ca2+, Na+) inhibitors and glutamic acid receptor inhibitors suppress cerebral infarction in animal experiments, they fail to show effect in clinical trials. Therefore, a neuroprotective agent having novel action mechanisms such as suppression of neuroinflammation and the like, which protects cerebral neuronal cells and suppresses enlargement of ischemic region is expected.
As for the suppression of inflammatory cytokine that has been reported to act neurotoxically in cerebral ischemic pathology, for example, when topical cerebral ischemic disorder of rat is aggravated by the administration of TNF-α in animal experiments, the cerebral ischemic disorder can be alleviated by a intraventricular administration of a TNF-α antibody (non-patent document 3). Moreover, it has been reported that DPH-067517, a TNF-α converting enzyme inhibitor, suppresses TNF-α expression on the cerebral infarction side and reduces neurological deficit and cerebral infarct volume in rat cerebral infarction model (non-patent document 4). In addition, a report has documented that injection of recombinant IL-1β into rat cerebral ventricle increases the cerebral infarction (non-patent document 5), and moreover, a cerebral ischemic disorder alleviating action by the administration of an IL-1β receptor antagonist (recombinant IL-1ra) is shown (non-patent document 6). In the clinical trial (Phase II), moreover, a cerebral ischemic disorder alleviating effect by administration of recombinant IL-1ra has been reported (non-patent document 7). However, there has been no report heretofore on a low-molecular-weight compound having a direct action on the IL-1β molecule per se, and the above-mentioned DPH-067517 cannot suppress the IL-1β expression on the cerebral infarction side.
As mentioned above, while many reports relating to individual inflammatory cytokines and cerebral infarction have been made, the effect thereof is not sufficient.
As a compound that inhibits TNF-α, the present inventors have found piperazine compounds having the properties shown in patent documents 1 and 2. Patent document 1 describes that the compound is effective for various diseases associated with various abnormalities in TNF-α production, TNF-α mediated diseases or diseases treatable with interleukin 10 (IL-10) (transplantation, osteoporosis, myocardial infarction, chronic cardiac failure, cardiac failure, ischemia-reperfusion injury and the like), and patent document 2 describes that the compound is effective for nonviral hepatitis. Moreover, non-patent documents 8 and 9 report that the compound is effective for hepatitis and rheumatoid arthritis models since the compound suppresses production of inflammatory cytokines TNF-α and IL-12 and promotes production of anti-inflammatory cytokine IL-10. However, the effectiveness of the compound for cerebral infarction and its treatment effect on cerebral infarction are not described or suggested.    patent document 1: WO99/19301    patent document 2: WO2005/103013    non-patent document 1: Dirnagl, U. et al., Trends. Neurosci., 22, 391-397 (1999)    non-patent document 2: Dirnagl, U. et al., Trends. Neurosci., 26, 248-254 (2003)    non-patent document 3: Barone, F. C. et al., Stroke, 28, 1223-1244 (1997)    non-patent document 4: Wang, X., et al., Molecular Pharmacology, 65, 890-896 (2004)    non-patent document 5: Yamazaki, Y. et al., Stroke, 26, 676-681 (1995)    non-patent document 6: Betz, A. L. et al., J. Cereb. Blood Flow Metab., 15, 547-551 (1995)    non-patent document 7: Emsley, H. C. A. et al., J. Neurol. Neurosurg. Psych., 76, 1366-1372 (2005)    non-patent document 8: Fukuda, T. et al., J. Pharmacy Pharmacol., 57, 1-6 (2005)    non-patent document 9: Hisadome, M. et al., Eur. J. Pharmacol., 497, 351-359 (2004)